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Pàgina inicial > Articles > Articles publicats > Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome |
Data: | 2016 |
Resum: | The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a "field effect" predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger "accelerated geroncogenesis" in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes "permissive" with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, α-ketoglutarate, NAD +, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the "install phase" that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the "geroncogenic risk" of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited "one-hit" metabolic "field effect" might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome. |
Ajuts: | Ministerio de Ciencia e Innovación SAF2012-38914 Ministerio de Ciencia e Innovación MTM2011-29342 Ministerio de Ciencia e Innovación PI15/00285 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1307 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1227 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-229 Instituto de Salud Carlos III PI15/-00285 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014 SGR1227 Ministerio de Economía y Competitividad SAF2012-38914 Ministerio de Economía y Competitividad CD12/00672 |
Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | BRCA1 ; Geroncogenesis ; Metabolism ; Cancer ; Metformin ; Gerotarget |
Publicat a: | Oncotarget, Vol. 7, issue 11 (March 2016) , p. 11959-11971, ISSN 1949-2553 |
13 p, 3.9 MB |